The trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines are an important class of compounds which exhibit opioid antagonist activity as a result of the 3-methyl substituent. Alvimopan (i.e., (+)-2-[(S)-benzyl-3-[4(R)-(3-hydroxyphenyl)-3(R),4-dimethylpiperidin-1-yl]propionamido]acetic acid), shown below, represents an example of this class of opioid antagonists. This compound is a peripherally-active antagonist which has a high affinity for the μ-opioid receptor in the lining of the gastrointestinal tract and is useful in the treatment of gastro-intestinal motility disorders. See, e.g., U.S. Pat. Nos. 5,270,328; 5,250,542; 5,159,081; and 5,434,171.

A synthesis of Alvimopan, partially outlined in FIG. 1, has been described in Werner et al., J. Org. Chem., 1996, 61, 587. The drug product was prepared in 12 steps and 6.2% yield from 1,3-dimethyl-4-piperidone as starting material. The synthesis includes the preparation of a (3R,4R)-3,4-dimethyl-4-(3-hydroxyphenyl)-piperidine nucleus (A), which was achieved in seven steps and 14.4% overall yield. While the next step, involving the Michael addition of (A) to methyl acrylate to produce intermediate (B), proceeds in good yield (96%), alkylation of the dianion of (B) with benzyl bromide proceeds with poor diastereoselectivity (47:53 mixture of the (3R,4R,αS)- and (3R,4R,αR)-isomers of the alkylation products, respectively). Consequently, the diastereomers require separation by recrystallization of their hydrochloride salts from methanol, resulting in low yields of intermediate (C) (34%). The poor diastereoselectivity of the alkylation step contributes to the low overall yield for the synthesis of Alvimopan.
In view of the importance of Alvimopan and related trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine derivatives and intermediates in the treatment of gastrointestinal motility disorders and other conditions involving μ-opioid receptors, improved syntheses are needed. Such improvements may include, for example, one or more of the following: enhanced diastereoselectivity of individual reaction steps, increased product yields, use of lower cost starting materials, lowered energy consumption (e.g., avoidance of reactions conducted at very high or low temperatures or pressures), reduction in the number of synthetic steps, improved scale-up conditions, and the like. The methods and compositions of the present invention are directed to these, as well as other important needs.